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Biomedical subjects

R A Brown

Publications and source records attributed to R A Brown.

At least 55 records · Page 3Linked to original sources

Reduction in matrix metalloproteinase production by tendon and synovial fibroblasts after a single exposure to 5-fluorouracil.

This study investigated the effect of treatment with 5min exposures to 5-fluorouracil (5-FU) on the production of matrix metalloproteinases (MMPs) by endotenon and synovial fibroblasts. Fibroblasts were grown from the flexor tendons of New Zealand White rabbits and were then exposed to varying concentrations (ranging from 0.25 mg x ml(-1)to 25 mg x ml(-1)of 5-FU for 5 min. The treated fibroblasts were suspended in a three-dimensional collagen lattice. The conditioned media from these collagen lattices were then analysed for MMP production using gelatin zymography on days 1, 3 and 7 after treatment. In the majority of cases this treatment produced a dose- and time-dependent reduction in total MMP production by both cell lines, specifically in the production of MMPs 2 and 9. This reduction was significant for most concentrations (P< or =0.01-P< or =0.05) when compared to phosphate-buffered-saline-treated controls. We conclude that 5-FU may reduce adhesions by limiting the migratory capacity of synovial fibroblasts (extrinsic healing).

Animals↗

Operative management of "hockey groin syndrome": 12 years of experience in National Hockey League players.

BACKGROUND: At the elite level of hockey, groin injuries can threaten a player's career. The aim of this review is to describe the clinical presentation and evaluate our operative approach to "hockey groin syndrome" in National Hockey League (NHL) players. METHODS: Between November 1989 and June 2000, 22 NHL players with debilitating groin pain underwent operative exploration. A repair, including ablation of the ilioinguinal nerve and reinforcement of the external oblique aponeurosis with a Goretex (W.L. Gore & Associates, Inc, Flagstaff, Ariz) mesh, was performed. Medical records were reviewed, and the players or their trainers were contacted by telephone after a mean follow-up period of 31.2 months to assess function, symptoms, and overall satisfaction. RESULTS: All patients had tearing of the external oblique aponeurosis, with branches of the ilioinguinal nerve emerging from the torn areas. At follow-up, 18 players (82%) had no pain, whereas 4 (18%) reported mild, intermittent pain. All 22 patients returned to playing hockey, with 19 (85%) able to continue their careers in the NHL. CONCLUSIONS: The "hockey groin syndrome," marked by tearing of the external oblique aponeurosis and entrapment of the ilioinguinal nerve, is a cause of groin pain in professional hockey players. Ilioinguinal nerve ablation and reinforcement of the external oblique aponeurosis successfully treats this incapacitating entity.

Adult↗

Influence of ATP-sensitive K+ channel modulation on the mechanical properties of diabetic myocardium.

ATP-sensitive K+ (KATP) channels are therapeutic targets for hypertension and diabetes. KATP channel opening elicits vasorelaxation and myocardial protection, whereas its closing stimulates insulin secretion. The cardiac KATP conductance is believed altered under diabetes. This study was to evaluate the influence of KATP channel openers and blocker on myocardial contractile dysfunction in diabetes. Adult rats were made diabetic with streptozotocin (55 mg/kg) and maintained for eight weeks. Contractile properties were studied using isolated papillary muscles in the absence or presence of KATP channel openers (BRL 38227 and pinacidil) and KATP blocker (glyburide). Experimental diabetes led to hyperglycemia, reduced growth, cardiac hypertrophy and hepatomegaly. Mechanical properties exhibited prolonged duration and reduced velocity of both contraction and relaxation in diabetic myocardium, characteristic of diabetic cardiomyopathy. Acute exposure to both KATP channel openers induced concentration-dependent negative inotropic effects (NIE) on myocardial contraction. The magnitude of the NIE was similar between the normal and diabetic groups and was fully reversible upon washout for BRL 38227 although not for pinacidil. Both KATP channel openers depressed the velocity of contraction and relaxation, whereas exerted no effect on the duration of contraction and relaxation, in myocardium from both groups. Acute exposure to glyburide, a KATP channel blocker, failed to alter any of the mechanical parameters measured. These data suggest that acute modulation of KATP channel with channel opener or blocker had little influence on diabetic cardiomyopathy, at least in the setting of multicellular preparations.

Adenosine Triphosphate↗

Influence of gender and diabetes on vascular and myocardial contractile function.

Premenopausal women have a lower cardiovascular risk than men or postmenopausal women. However, this "female advantage" is lost in diabetes, a condition characterized by cardiac and vascular contractile dysfunction. This study was designed to compare the influence of diabetes on vascular and myocardial contractile function between genders. Adult male and female rats were made diabetic with streptozotocin (55 mg/kg) and maintained for 8 weeks. Tension development was examined in thoracic aortic rings and left ventricular papillary muscles. KCl-induced vasoconstriction, acetylcholine (ACh)-induced endothelium dependent or sodium nitroprusside (SNP)-induced endothelium-independent vasorelaxation, duration and maximal velocity of myocardial contraction and relaxation duration (TPT/RT90 and +/- VT) were similar between males and females. Diabetes augmented KCl-induced vasoconstriction at low doses, reduced SNP-induced vasorelaxation and had little effect on ACh-induced vasorelaxation in aortic rings from both genders. Diabetes prolonged TPT and RT90 in both genders, and reduced +/- VT in males but not females. Acute increase in extracellular Ca2+ (2.7 mM to 5.4 mM) shortened TPT in diabetic myocardium from both genders, whereas it had no effect on other myocardial mechanical indices in normal or diabetic groups of either gender. In addition, acute exposure to the Na+/K(+)-ATPase inhibitor ouabain shortened TPT/RT90 and enhanced +/- VT in myocardium from normal female, whereas it had no effect on male or diabetic myocardium. In conclusion, these data suggest that in the vasculature, there is no difference in diabetes-induced contractile dysfunction between genders, however several gender-specific differences are evident in the myocardium.

Acetylcholine↗

Survivors of childhood abuse: their reported experiences with professional help.

This article analyzes the self-reports of 384 adults who responded to a survey of people abused physically, sexually, or emotionally by family members in childhood. Most of the respondents sought help as adults from social workers and other mental health professionals for the long-term effects of their abusive experiences. This article analyses the reports of their help-seeking experiences against a backdrop of the reports of clinicians and researchers on working with survivors, as reported in the literature. Although survivors of childhood abuse often are described as having difficulty relating to professionals, these respondents persisted in seeking help and tended to report at least one experience with professional services that was very helpful. Their self-esteem and family functioning in adulthood was associated with having had a very helpful professional or service provider. The findings describe the responses most valued by survivors, as well as their views of the limitations of available services.

Adult↗

Natural course of alcohol use disorders from adolescence to young adulthood.

OBJECTIVES: To examine the course of alcohol use disorder (AUD) and determine the extent to which AUD in adolescence is a risk factor for AUD and other psychopathology in young adulthood. METHOD: Nine hundred forty participants from a large community sample in western Oregon were interviewed twice during adolescence (14-18 years of age the first assessment; between 1987 and 1991) and once at age 24 (1993-1999). Between 1995 and 1998, parents were assessed for lifetime AUD. Participants were classified into nonproblematic use (NON), problem drinker (PROB) (symptoms of AUD but no diagnosis), and AUD groups. RESULTS: Adolescent AUD significantly predicted AUD, substance use disorder, depression, and elevated levels of antisocial and borderline personality disorder symptoms by age 24. Compared with the NON group, adolescents in the PROB group were at increased risk for AUD, substance use disorder, depression, and antisocial personality disorder symptoms. However, the PROB group had lower rates of future AUD and antisocial personality disorder symptoms than the adolescent AUD group. Gender interactions were nonsignificant. Daily smoking and conduct/oppositional defiant disorders predicted future AUD, when adolescent AUD and other disorders were controlled. Paternal, but not maternal, AUD was associated with greater risk of future AUD. CONCLUSIONS: For the majority of adolescents, AUD are not benign conditions that resolve over time. Assessment, treatment, and prevention recommendations are discussed.

Adolescent↗

Comparative quantitation of cytomegalovirus (CMV) DNA in solid organ transplant recipients with CMV infection by using two high-throughput automated systems.

Cytomegalovirus (CMV) DNA quantitation in clinical specimens is progressively becoming a cornerstone in the diagnosis and management of CMV infection in the immunocompromised host. We evaluated two automated and reproducible PCR tests, the LightCycler (Roche Molecular Biochemicals, Indianapolis, Ind.) and the COBAS AMPLICOR CMV Monitor (Roche Diagnostics, Pleasanton, Calif.), for the detection of CMV DNA in blood samples from transplant recipients with CMV infection as determined by shell vial culture. Following a log transformation analysis, the mean CMV DNA in plasma (PL), whole blood (WB), peripheral blood leukocytes (PBL), and peripheral blood mononuclear cells (PBMC) using the LightCycler was 6.79 copies per ml, 7.23 copies per ml, 6.38 copies per 2 x 10(6) cells, and 6.27 copies per 2 x 10(6) cells, respectively. This compares to 7.86 copies per ml, 8.37 copies per ml, 7.59 copies per 2 x 10(6) cells, and 7.44 copies per 2 x 10(6) cells, respectively, using COBAS AMPLICOR CMV Monitor. While higher CMV DNA levels were observed for the various blood compartments analyzed using COBAS AMPLICOR CMV Monitor, a high degree of correlation was evident between the two automated systems (jackknife correlation r = PL 0.77 [95% confidence interval (CI); 0.64, 0.90], WB 0.77 [95% CI; 0.62, 0.92], PBL 0.77 [95% CI; 0.67, 0.88], and PBMC 0.81 [95% CI; 0.72, 0.89], all P < 0.001). Therefore, we conclude that either automated diagnostic system is accurate for CMV DNA quantitation.

Adult↗

Vagotomy attenuates tumor necrosis factor-alpha-induced sleep and EEG delta-activity in rats.

Much evidence suggests that tumor necrosis factor-alpha (TNF-alpha) is involved in the regulation of physiological sleep. However, it remains unclear whether peripheral administration of TNF-alpha induces sleep in rats. Furthermore, the role of the vagus nerve in the somnogenic actions of TNF-alpha had not heretofore been studied. Four doses of TNF-alpha were administered intraperitoneally just before the onset of the dark period. The three higher doses of TNF-alpha (50, 100, and 200 microg/kg) dose dependently increased nonrapid eye movement sleep (NREMS), accompanied by increases in electroencephalogram (EEG) slow-wave activity. TNF-alpha increased EEG delta-power and decreased EEG alpha- and beta-power during the initial 3 h after injection. In vagotomized rats, the NREMS responses to 50 or 100 microg/kg of TNF-alpha were attenuated, while significant TNF-alpha-induced increases in NREMS were observed in a sham-operated group. Moreover, the vagotomized rats failed to exhibit the increase in EEG delta-power induced by TNF-alpha intraperitoneally. These results suggest that peripheral TNF-alpha can induce NREMS and vagal afferents play an important role in the effects of peripheral TNF-alpha and EEG synchronization on sleep. Intraperitoneal TNF-alpha failed to affect brain temperature at the doses tested, thereby demonstrating that TNF-alpha-induced sleep effects are, in part, independent from its effects on brain temperature. Results are consistent with the hypothesis that a cytokine network is involved in sleep regulation.

Animals↗

Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits.

Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalographic (EEG) slow waves during the initial 9-h postinjection period, then, during hours 10-23 postinjection, reduced EEG slow-wave activity. Current data support the notion that the brain cytokine network is involved in the regulation of sleep.

Animals↗

Interleukin-18 promotes sleep in rabbits and rats.

Interleukin (IL)-1beta is involved in physiological sleep regulation. IL-18 is a member of the IL-1 family, and its signal-transduction mechanism is similar to that of IL-1. Therefore, we hypothesized that IL-18 might also be involved in sleep regulation. Three doses of IL-18 (10, 100, and 500 ng) were injected intracerebroventricularly (icv) into rabbits at the onset of the dark period. The two higher doses of IL-18 markedly increased non-rapid eye movement sleep (NREMS), accompanied by increases in brain temperature (Tbr). These effects were lost after the heat inactivation of IL-18. The 500 ng of IL-18 injection during the light period also increased NREMS and Tbr. Similar results were obtained after icv injection of 100 ng of IL-18 into rats. Furthermore, intraperitoneal injection of 30 microg/kg of IL-18 slightly, but significantly, increased NREMS, whereas it significantly decreased electroencephalogram slow-wave activity in rats. Intraperitoneal IL-18 failed to induce fever. An anti-human IL-18 antibody had little effect on spontaneous sleep in rabbits, although the anti-IL-18 antibody significantly attenuated muramyl dipeptide-induced sleep. These data suggest that IL-18 is involved in mechanisms of sleep responses to infection.

Acetylmuramyl-Alanyl-Isoglutamine↗

The influence of gender, diabetes, and acetaldehyde on the intrinsic contractile properties of isolated rat myocardium.

Diabetes is associated with ventricular dysfunction. Ethanol consumption increases the risk of cardiovascular disease among diabetics. Acetaldehyde (ACA), the main ethanol metabolite, depresses cardiac contraction and contributes to ethanol-induced cardiac dysfunction. This study examined the influence of gender and diabetes on ACA-induced myocardial dysfunction. Adult male and female rats were made diabetic with streptozotocin (55 mg/kg). Left ventricular papillary muscles were isolated and stimulated to contract at 0.5 Hz. The mechanical parameters measured were peak tension development, time-to-peak tension (TPT), time-to-90% relaxation (RT90), and maximum velocities of tension development and decline (+/-VT). TPT and RT90 were comparably similar between genders. The +/-VT appeared to be slower in myocardium from female rats when compared to that of male counterparts, although the difference was not significant. Experimental diabetes elicited severe hyperglycemia, cardiac hypertrophy, hepatomegaly, and renal hypertrophy in both male and female animals. Myocardial mechanical properties exhibited prolonged TPT and RT90 in diabetic myocardium from both genders. The +/-VT was significantly reduced by diabetes in male but not in female myocardium. Acute ACA exposure decreased myocardial tension development and the +/-VT and shortened TPT and RT90 in myocardium from normal and diabetic rats of both genders. The ACA-induced depressant response on tension development was slightly enhanced by the diabetic state. In conclusion, these data suggest that the development of diabetes-induced myocardial dysfunction is similar between male and female animals and that the ACA-induced myocardial depressant action may be affected by diabetes but not by gender.

Acetaldehyde↗

Relationship among alcohol use, depression, smoking behavior, and motivation to quit smoking with hospitalized smokers.

Relationships among depression, alcohol use, and motivation to quit smoking were examined in a sample of 350 hospitalized smokers. Multivariate multiple regression and logistic regression analyses indicated that participants with depressed mood were more likely to have a history of problematic drinking. Participants with depressed mood and a history of problematic drinking were more likely to be nicotine dependent and anticipated greater difficulty refraining from smoking while hospitalized. Alcohol use in heavier amounts was associated with a decreased concern with negative aspects of smoking, whereas history of depression was associated with increased concern in that area. Finally, current drinking was associated with increased confidence in quitting in 1 month whereas depressed mood was associated with decreased confidence in quitting. Overall, depression and alcohol use had stronger associations with smoking-related variables than with smoking cessation motivation variables.

Alcoholism↗

Naltrexone and cue exposure with coping and communication skills training for alcoholics: treatment process and 1-year outcomes.

BACKGROUND: Promising treatments for alcoholics include naltrexone (NTX), cue exposure combined with urge-specific coping skills training (CET), and communication skills training (CST). This study investigated the effects of combining these elements as treatment adjuncts. METHODS: A 2 x 2 design investigated the effects of CET combined with CST, as compared with an education and relaxation control treatment, during a 2-week partial hospital program (n = 165) followed by 12 weeks of NTX (50 mg/day) or placebo during aftercare (n = 128). Drinking outcomes were assessed at 3, 6, and 12 months after discharge from the partial hospital. Process measures included urge, self-efficacy (confidence about staying abstinent in risky situations), and self-reported coping skills. Medically eligible alcohol-dependent patients were recruited. RESULTS: Among those compliant with medication on at least 70% of days, those who received NTX had significantly fewer heavy drinking days and fewer drinks on days that they drank than those receiving placebo during the medication phase but not during the subsequent 9 months. CET/CST-condition patients were significantly less likely to report a relapse day and reported fewer heavy drinking days at the 6- and 12-month follow-ups than patients in the control treatment. Interactions of medication with behavioral treatments were not significant. Process measures showed that NTX resulted in lower weekly urge ratings, and those in CET/CST used more of the prescribed coping skills after treatment, reported fewer cue-elicited urges, and reported more self-efficacy in a posttest role-play test. Drinking reductions at 3, 6, and 12 months correlated with more use of coping skills, lower urge, and higher self-efficacy. CONCLUSIONS: The results suggest the probable value of keeping alcoholics on NTX for longer periods of time and the importance of increasing compliance with NTX. They also support the earlier promising effects of CET and CST as adjuncts to treatment programs for alcoholics by maintaining treatment gains over at least a year. The value of the urge-specific and general coping skills and of self-efficacy and urge constructs was demonstrated in their association with drinking outcomes.

Adaptation, Psychological↗

Loss of cardiac contractile response to tetrahydropapaveroline with advanced age and hypertension.

Tetrahydropapaveroline (THP), a condensation product of ethanol-derived acetaldehyde, potentiates cardiac function through beta-adrenoceptor. We have recently shown that THP-induced cardiac contractile action is likely due to its action at the single myocyte level, and is markedly diminished during early hypertension. Cardiac function alters with advanced age reminiscent of hypertension. This study was to examine cardiac contractile response to THP with advanced age and hypertension. Left ventricular papillary muscles and myocytes were isolated from normotensive (WKY) or hypertensive (SHR) rats, and stimulated to contract at 0.5 Hz. Mechanical parameters evaluated include: peak tension developed (PTD)/peak shortening (PS), time-to-PTD/PS (TPT/TPS), time-to-90% relaxation/relengthening (RT90/TR90), and maximal velocities of contraction/relaxation (+/- VT/+/- dLdt). Intracellular Ca2+ transients were measured as fura-2 fluorescence intensity changes (AFFI). THP (0.1-100 microM) increased PTD in 10- but not 36-wk-old WKY rat myocardium. THP elicited positive, negative or no response on PS in myocytes from 10-wk WKY, 36-wk WKY, and 36-wk SHR groups, respectively. Interestingly, THP elicited discrepant response on intracellular Ca2+ transient compared with that of myocyte shortening. THP increased AFFI in 10-wk WKY and 36-wk SHR myocytes while exhibiting a significant inhibiting action in 36-wk WKY myocytes. Lastly, THP shortened TPT/TPS, RT90/TR90 and increased +VT in all animal groups. These results indicate that the THP-induced myocardial contractile response is altered in advanced age and hypertension, in a manner similar to early stage of hypertension. It is possible that altered intracellular Ca2+ responsiveness may be involved in THP-induced action.

Aging↗

Performance of air sparging systems: a review of case studies.

Fluor Daniel GTI (now IT Corporation) has compiled a database of 49 completed in-situ air sparging case studies. Air sparging is a commonly used remediation technology which volatilizes and enhances aerobic biodegradation of contamination in groundwater and saturated zone soil. The air sparging database was compiled to address questions regarding the effectiveness and permanence of air sparging, and to provide predictive indicators of air sparging success to aid in optimization of existing and future air sparging systems. In each case study, groundwater concentrations were compared before sparging was initiated, just before sparging was terminated, and in the months following shutdown of the sparging system. The case studies included both chlorinated solvents and petroleum hydrocarbon contamination, and covered a wide range of soil conditions and sparge system parameters. In many cases, air sparging achieved a substantial and permanent decrease in groundwater concentrations. Successful systems were achieved with both chlorinated and petroleum contamination, both sandy and silty soils, and both continuous and pulsed flow sparging. In other cases, however, a significant rebound of groundwater concentrations was observed after sparging was terminated. Rebound sometimes required 6 to 12 months to develop fully. Rebound was more frequently observed at sites contaminated with petroleum hydrocarbons than with chlorinated solvents. Petroleum-contaminated sites were more likely to rebound when initial groundwater contamination levels were high enough to suggest the presence of LNAPL or a smear zone of residual LNAPL. Rebound at petroleum sites appeared to be minimized by a high density of sparge wells addressing the entire source area and a high sparge air injection rate. In some cases, rebound appeared to be related to a rising water table.

Aerobiosis↗

Molecular responses of human dermal fibroblasts to dual cues: contact guidance and mechanical load.

Fibroblast contraction in wound healing involves the interaction of several cell types, cytokines, and extracellular matrix molecules. We have previously developed fibroblast alignment models using precise uniaxial mechanical loads in 3D culture and using contact guidance on fibronectin strands. Our aim here was to use contact guidance to place fibroblasts in their potentially most sensitive configuration, i.e., perpendicular to the axis of loading, to present cells with conflicting guidance cues. Gene expression at the mRNA level of cells recovered from different zones of the 3D collagen gel (with distinct orientation) was determined by quantitative RT-PCR for the matrix proteases MMP1, 2, and 3, and inhibitors TIMP1 and 2. Our results show a 2-, 4-, and 3-fold increase in MMP1, 2, and 3, respectively, in the non-aligned strain zone, relative to the aligned strain zone. These results suggest that cells unable to align to applied loads remodel their matrix far more rapidly than orientated cells. Where fibroblasts were held in an alignment perpendicular to the applied load by contact guidance, the fall in MMP mRNA expression was largely abolished, indicating that these cells remained in a mechano-activated state. The protease inhibitors TIMP1 and 2 were poorly mechano-responsive, further suggesting that changes in MMP expression result in functional matrix remodelling. These results indicate how mechanical loading in tissues may influence matrix remodelling, particularly under conflicting guidance cues.

Cell Adhesion↗

Low concentrations of fibrinogen increase cell migration speed on fibronectin/fibrinogen composite cables.

Optimal cell migration rate in a given direction (velocity) is a function of speed and directional persistence. Migration speed has been reported to be a function of adhesion strength such that optimal cell migration occurs where the cell is able to form enough stable attachments for good traction while allowing attachments at the trailing end to be broken during locomotion. This is particularly important in peripheral nerve regeneration where rapid Schwann cell recruitment across the injury site will lead to better functional recovery and reduced end organ atrophy. The aim here was to investigate the effects of changing adhesion properties of Fn materials by adding fibrinogen in order to design an optimal material for repair processes. Cell migration on Fn/Fg-cables increased with increasing content of %Fg to a peak cell migration velocity (Schwann cells) of 49 microm/h, at 50% Fg. Further increases in Fg content hindered cell migration. Vinculin-rich attachment plaques were reduced in a dose-dependent manner as the content of %Fg was increased whilst cells at the optimum Fg proportion for cell migration were moderately well spread. These results support the idea that optimum cell migration rates occur at intermediate attachment conditions, in this case at 50% Fg. These results show that incorporation of Fg into Fn-based materials will enhance the speed of Schwann cell migration and this would be likely to improve peripheral nerve regeneration. Indeed, directionally aligned Fn-based materials can now be engineered to give optimal cell velocity during repair cell recruitment in a range of tissue repair or tissue engineering applications.

Animals↗

Testosterone decreases CA1 plasticity in vivo in gonadectomized male rats.

Estrogen has been reported to enhance CA1 functional plasticity in adult rats, as measured by the induction of long-term potentiation (LTP). In the present study, the effects of androgens on CA1 LTP were assessed in adult male Sprague-Dawley rats in vivo following peripubertal castration. Castrated rats with cholesterol implants showed significantly greater plasticity, both in degree and duration of potentiation, than castrated rats given testosterone or dihydrotestosterone implants. An LTP paradigm reported to produce decremental LTP in vitro produced nondecremental LTP in androgen-deprived rats, but decremental LTP in androgen-treated rats. These results suggest that androgens, unlike estrogens, act to reduce CA1 plasticity in the adult rat.

Animals↗